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A Ubl/ubiquitin switch in the activation of Parkin
Author(s) -
Sauvé Véronique,
Lilov Asparouh,
Seirafi Marjan,
Vranas Marta,
Rasool Shafqat,
Kozlov Guennadi,
Sprules Tara,
Wang Jimin,
Trempe JeanFrançois,
Gehring Kalle
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201592237
Subject(s) - biology , parkin , ubiquitin , ubiquitin protein ligases , genetics , microbiology and biotechnology , ubiquitin ligase , ubiquitins , computational biology , gene , medicine , disease , parkinson's disease
Mutations in Parkin and PINK 1 cause an inherited early‐onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK 1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK 1 kinase activity releases the auto‐inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho‐ubiquitin ( pU b) and the ubiquitin‐like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS , we show that pU b binds to RING 1 of Parkin at a site formed by His302 and Arg305. pU b binding promotes disengagement of the Ubl from RING 1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Δ86–130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING 1. These mutations mimic pU b binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin‐conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pU b binding.